Novel modulators of cortical dopaminergic- and nmda-receptor-mediated glutamatergic neurotransmission

ABSTRACT

The present invention relates to novel substituted phenoxyethylamine derivatives, useful as modulators of cortical and basal ganglia dopaminergic and N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation of U.S. patent applicationSer. No. 14/112,080, filed Oct. 16, 2013, which is a U.S. National PhaseApplication of International Application No. PCT/EP2012/056959, filedApr. 17, 2012, which claims priority to Danish Patent Application No. PA2011 70187, filed Apr. 19, 2011; U.S. Provisional Patent Application No.61/476,810, filed Apr. 19, 2011; and Danish Patent Application No. PA2011 70495, filed Sep. 6, 2011, all of which applications areincorporated herein fully by this reference.

REFERENCE TO SEQUENCE LISTING

The Sequence Listing submitted Jan. 23, 2015 as a text file named“37441_(—)0001U2_Sequence_Listing.txt,” created on Jan. 19, 2015, andhaving a size of 1,781 bytes is hereby incorporated by referencepursuant to 37 C.F.R. §1.52(e)(5).

TECHNICAL FIELD

The present invention relates to novel substituted phenoxy-ethyl-aminederivatives, useful as modulators of cortical and basal gangliadopaminergic and N-methyl-D-aspartate (NMDA) receptor-mediatedglutamatergic neurotransmission. In other aspects the invention relatesto the use of these compounds in a method for therapy and topharmaceutical compositions comprising the compounds of the invention.

BACKGROUND ART

Dopamine is a neurotransmitter in the brain. Since this discovery, madein the 1950's, the function of dopamine in the brain has been intenselyexplored. To date, it is well established that dopamine is essential inseveral aspects of brain function including motor, cognitive, sensory,emotional and autonomous functions (e.g. regulation of appetite, bodytemperature, sleep). Thus, modulation of dopaminergic function may bebeneficial in the treatment of a wide range of disorders affecting brainfunctions. In fact, drugs that act, directly or indirectly at centraldopamine receptors are commonly used in the treatment of neurologicaland psychiatric disorders, e.g. Huntington and Parkinson's disease andschizophrenia.

Antipsychotic drugs (or neuroleptics) are a class of compounds withdiverse effects on different receptor systems. However, they have incommon the ability to block dopamine D₂ receptors in the basal ganglia(i.e. striatum) and are used to manage psychosis (including delusions orhallucinations, as well as disordered thought), particularly inschizophrenia and bipolar disorder.

The cerebral cortex encompasses several major regions that are involvedin higher functions such as thought, feelings, memory and planning.Biogenic amines such as dopamine are important for mammalian corticalfunction. The ascending dopamine pathways innervate the cortex. Primaryor secondary dysfunctions in the activity of these pathways lead todysregulation of the activity at dopamine in these brain areas andsubsequently to manifestations of psychiatric and neurological symptoms.Both dopamine D₁ and N-methyl-D-aspartate (NMDA) receptors in theprefrontal cortex play a critical role in synaptic plasticity, memorymechanisms, and cognition.

Huntington's disease (HD) is a rare neurodegenerative disorder of thecentral nervous system characterized by progressive deterioration ofmotor and cognitive functions as well as behavioural and psychiatricdisturbances. It is well established that certain aspect of dopaminergicfunctions are also affected in Huntington's disease. Neuropathologicalchanges in Huntington's disease involve prominent cell loss and atrophyin the striatum but also in many other brain regions such as the cortex,substantia nigra, hypothalamus, cerebellum and thalamus.

In HD, glutamate and dopamine (DA) transmission is altered, which islikely to induce an imbalance in activity of the direct and indirectpathways and to contribute to the motor, cognitive, and psychiatricsymptoms of HD (i.e. communication between the cortex and striatum,Capeda et al; ASN Neuro 2010 2 (2) e00033). Therefore, compounds whichcan strengthen the cortical dopamine and NMDA transmission, and exertantagonism of excessive subcortical dopamine transmission, can balanceaberrant functioning in the cortico-striato-thalamic network controllingmotor functions (Alexander et al; Ann. Rev. Neurosci. 1986 9 357-381).

JP 2006-193494 (Dainippon Ink and Chemicals, Inc) describes certainquaternary ammonium compounds useful as therapeutic agent for heartdiseases.

WO 2009/133107 (NSAB, Filial af NeuroSearch Sweden AB, Sverige)describes certain 1-(2,3-dihydro-1,4-benzodioxin-2-yl)methanaminederivatives, WO 2009/133109 (NSAB, Filial af NeuroSearch Sweden AB,Sverige) describes certain1-(2,3-dihydro-1,4-benzodioxin-2-yl)methanamine derivatives, and WO2009/133110 (NSAB, Filial af NeuroSearch Sweden AB, Sverige) describescertain 1-(4H-1,3-benzodioxin-2-yl)methanamine derivatives, useful asmodulators of dopamine neurotransmission, and more specifically asdopaminergic stabilizers. However, the phenoxy-ethyl-amine derivativesof the present invention have not previously been reported.

SUMMARY OF THE INVENTION

The object of the present invention is to provide novel pharmaceuticallyactive compounds, especially useful in treatment of disorders in thecentral nervous system. A further object is the provision of compoundsfor modulation of dopaminergic and glutamatergic systems in themammalian brain, including human brain.

In its first aspect, the invention provides a phenoxy-ethyl-aminederivative of Formula 1

a stereoisomer or a mixture of its stereoisomers, or an N-oxide thereof,or a fully or partially deuterated analog thereof, or a pharmaceuticallyacceptable salt thereof, wherein R¹, R², R³, R⁴, R′ and R″ are asdefined below.

In its second aspect, the invention provides a pharmaceuticalcomposition, comprising a therapeutically effective amount of aphenoxy-ethyl-amine derivative of the invention, a stereoisomer or amixture of its stereoisomers, or an N-oxide thereof, or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, excipient or diluent.

In a further aspect, the invention provides the use of aphenoxy-ethyl-amine derivative of the invention, a stereoisomer or amixture of its stereoisomers or an N-oxide thereof, or apharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition for the treatment, prevention or alleviationof a disease or a disorder or a condition of a mammal, including ahuman, which disease, disorder or condition is responsive to responsiveto modulation of dopaminergic and glutamatergic function in the centralnervous system.

In a still further aspect, the invention relates to a method fortreatment, prevention or alleviation of a disease or a disorder or acondition of a living animal body, including a human, which disorder,disease or condition is responsive to modulation of dopaminergic andglutamatergic function in the central nervous system, which methodcomprises the step of administering to such a living animal body in needthereof a therapeutically effective amount of a phenoxy-ethyl-aminederivative of the invention, a stereoisomer or a mixture of itsstereoisomers, or an N-oxide thereof, or a pharmaceutically acceptablesalt thereof.

Other aspects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DESCRIPTION OF THE INVENTION Phenoxyethylamine Derivatives

In its first aspect the present invention provides phenoxy-ethyl-aminederivatives of Formula 1

a stereoisomer or a mixture of its stereoisomers, or an N-oxide thereof,or a fully or partially deuterated analog thereof, or a pharmaceuticallyacceptable salt thereof, wherein

R¹ represents CH₃ or CF₃;

R² is selected from the group consisting of C₁-C₄-alkyl, allyl,CH₂CH₂OCH₃, C(CH₃)₂CH₂CH₃, CH₂-cyclopropyl, cyclobutyl, cyclopentyl,CH₂CH₂CH₂F, CH₂CH₂CHF₂, CH₂CH₂F, 3,3,3-trifluoropropyl and4,4,4-trifluorobutyl; and

R³ is selected from the group consisting of H, CH₃ and CH₂CH₃; or

R² and R³ together form CH₂(CH₂)CH₂ or CH₂(CH₂)₃CH₂;

R⁴ represents F or Cl; and

R′ and R″ independently represent hydrogen or methyl.

In a preferred embodiment the phenoxy-ethyl-amine derivative of theinvention is a compound of Formula 1a

a stereoisomer or a mixture of its stereoisomers, or an N-oxide thereof,or a pharmaceutically acceptable salt thereof, wherein

R¹ is selected from the group consisting of CH₃ or CF₃;

R² is selected from the group consisting of C₁-C₄ alkyl, allyl,CH₂CH₂OCH₃, C(CH₃)₂CH₂CH₃, CH₂-cyclopropyl, CH₂CH₂CH₂F, CH₂CH₂CHF₂,CH₂CH₂F, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl;

R³ is selected from the group consisting of H, CH₃ and CH₂CH₃; and

R⁴ is selected from the group consisting of F and Cl.

In another preferred embodiment the phenoxy-ethyl-amine derivative ofthe invention is a compound of Formula 1a, a stereoisomer or a mixtureof its stereoisomers, or an N-oxide thereof, or a pharmaceuticallyacceptable salt thereof, wherein

R¹ is selected from the group consisting of CH₃ or CF₃;

R² is selected from the group consisting of C₁-C₄ alkyl, allyl,CH₂CH₂OCH₃, C(CH₃)₂CH₂CH₃, CH₂-cyclopropyl, cyclobutyl, cyclopentyl,CH₂CH₂CH₂F, CH₂CH₂CHF₂, CH₂CH₂F, 3,3,3-trifluoropropyl and4,4,4-trifluorobutyl;

R³ is selected from the group consisting of H, CH₃ and CH₂CH₃;

or R² and R³ together form CH₂(CH₂)₃CH₂; and

R⁴ is selected from the group consisting of F and Cl.

In a third preferred embodiment the phenoxy-ethyl-amine derivative ofthe invention is a compound of Formula 1 or 1a, a stereoisomer or amixture of its stereoisomers, or an N-oxide thereof, or apharmaceutically acceptable salt thereof, wherein R¹ represents CH₃ orCF₃.

In a more preferred embodiment R¹ represents CH₃.

In another more preferred embodiment R¹ represents CF₃.

In a fourth preferred embodiment the phenoxy-ethyl-amine derivative ofthe invention is a compound of Formula 1 or 1a, a stereoisomer or amixture of its stereoisomers, or an N-oxide thereof, or apharmaceutically acceptable salt thereof, wherein R² is selected fromthe group consisting of C₁-C₄-alkyl, allyl, CH₂CH₂OCH₃, C(CH₃)₂CH₂CH₃,CH₂-cyclopropyl, cyclobutyl, cyclopentyl, CH₂CH₂CH₂F, CH₂CH₂CHF₂,CH₂CH₂F, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl.

In a more preferred embodiment R² is selected from the group consistingof C₁-C₄-alkyl, CH₂-cyclopropyl, cyclobutyl and cyclopentyl.

In another more preferred embodiment R² represents C₁-C₄-alkyl.

In a third more preferred embodiment R² represents CH₂-cyclopropyl.

In a fourth more preferred embodiment R² represents cyclobutyl.

In a fifth more preferred embodiment R² represents cyclopentyl.

In a fifth preferred embodiment the phenoxy-ethyl-amine derivative ofthe invention is a compound of Formula 1 or 1a, a stereoisomer or amixture of its stereoisomers, or an N-oxide thereof, or apharmaceutically acceptable salt thereof, wherein R³ is selected fromthe group consisting of H and CH₃.

In a more preferred embodiment R³ represents H.

In another more preferred embodiment R³ represents CH₃.

In a sixth preferred embodiment the phenoxy-ethyl-amine derivative ofthe invention is a compound of Formula 1 or 1a, a stereoisomer or amixture of its stereoisomers, or an N-oxide thereof, or apharmaceutically acceptable salt thereof, wherein R² and R³ togetherform CH₂(CH₂)CH₂ or CH₂(CH₂)₃CH₂.

In a more preferred embodiment R² and R³ together form CH₂(CH₂)CH₂.

In another more preferred embodiment R² and R³ together formCH₂(CH₂)₃CH₂.

In a seventh preferred embodiment the phenoxy-ethyl-amine derivative ofthe invention is a compound of Formula 1 or 1a, a stereoisomer or amixture of its stereoisomers, or an N-oxide thereof, or apharmaceutically acceptable salt thereof, wherein R⁴ represents F or Cl.

In a more preferred embodiment R⁴ represents F.

In another more preferred embodiment R⁴ represents Cl.

In an eight preferred embodiment the phenoxy-ethyl-amine derivative ofthe invention is a compound of Formula 1, a stereoisomer or a mixture ofits stereoisomers, or an N-oxide thereof, or a pharmaceuticallyacceptable salt thereof, wherein R′ and R″ independently representhydrogen or methyl.

In a more preferred embodiment one of R′ and R″ represents hydrogen; andthe other of R′ and R″ represents methyl.

In another more preferred embodiment R′ represents hydrogen; and R″represents methyl.

In a third more preferred embodiment R′ represents methyl; and R″represents hydrogen.

In a fourth more preferred embodiment R′ and R″ both representshydrogen.

In a fifth more preferred embodiment R′ and R″ both represents methyl.

In a most preferred embodiment the phenoxy-ethyl-amine derivative of theinvention is

-   N-[2-(3-Fluoro-5-methylsulfonyl-phenoxy)ethyl]propan-1-amine;-   N-[2-(3-Fluoro-5-methylsulfonyl-phenoxy)ethyl]butan-1-amine;-   N-Ethyl-2-(3-fluoro-5-methylsulfonyl-phenoxy)ethanamine;-   N-[2-(3-Fluoro-5-methylsulfonyl-phenoxy)ethyl]-N-methyl-propan-1-amine;-   N-[2-(3-Chloro-5-methylsulfonyl-phenoxy)ethyl]propan-1-amine;-   N-[2-(3-Fluoro-5-methylsulfonyl-phenoxy)ethyl]butan-2-amine;-   N-[2-(3-Fluoro-5-methylsulfonyl-phenoxy)ethyl]cyclopentamine;-   N-[2-(3-Fluoro-5-methylsulfonyl-phenoxy)ethyl]-2-methyl-butan-2-amine;-   N-[2-(3-Fluoro-5-methylsulfonyl-phenoxy)ethyl]cyclobutamine;-   N-[2-(3-Fluoro-5-methylsulfonyl-phenoxy)ethyl]propan-2-amine;-   1-[2-(3-Fluoro-5-methylsulfonyl-phenoxy)ethyl]piperidine;-   N,N-Diethyl-2-(3-fluoro-5-methylsulfonyl-phenoxy)ethanamine;-   N-1,1-di-deuterium-propyl-[2-(3-fluoro-5-methanesulfonyl-phenoxy)-ethyl]-amine;-   N-(Cyclopropylmethyl)-N-{2-[3-fluoro-5-(methylsulfonyl)-phenoxy]ethyl}amine;-   N-{2-[3-Fluoro-5-(methylsulfonyl)phenoxy]ethyl}-N-isobutylamine;-   1-[2-(3-Fluoro-5-methylsulfonyl-phenoxy)ethyl]azetidine;-   1-(3-Fluoro-5-methylsulfonyl-phenoxy)-N-propyl-propan-2-amine; or-   2-(3-Fluoro-5-methylsulfonyl-phenoxy)-N-propyl-propan-1-amine;

a stereoisomer or a mixture of its stereoisomers, or an N-oxide thereof,or a pharmaceutically acceptable salt thereof.

Any combination of two or more of the embodiments as described above isconsidered within the scope of the present invention.

DEFINITION OF TERMS

In the context of this invention C₁-C₄-alkyl means a straight chain orbranched chain of one to four carbon atoms, including but not limitedto, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl.

The term “allyl” refers to the group —CH₂—CH═CH₂.

The term “treatment” as used herein means the management and care of apatient for the purpose of combating a disease, disorder or condition.The term is intended to include the delaying of the progression of thedisease, disorder or condition, the alleviation or relief of symptomsand complications, and/or the cure or elimination of the disease,disorder or condition. The patient to be treated is preferably a mammal,in particular a human being.

The terms “disease”, “condition” and “disorder” as used herein are usedinterchangeably to specify a state of a patient which is not the normalphysiological state of man.

The term “medicament” as used herein means a pharmaceutical compositionsuitable for administration of the pharmaceutically active compound to apatient.

The term “pharmaceutically acceptable” as used herein means suited fornormal pharmaceutical applications, i.e. giving rise to no adverseevents in patients etc.

The term “effective amount” as used herein means a dosage which issufficient in order for the treatment of the patient to be effectivecompared with no treatment.

The term “therapeutically effective amount” of a compound as used hereinmeans an amount sufficient to cure, alleviate or partially arrest theclinical manifestations of a given disease and its complications. Anamount adequate to accomplish this is defined as “therapeuticallyeffective amount”. Effective amounts for each purpose will depend on theseverity of the disease or injury as well as the weight and generalstate of the subject. It will be understood that determining anappropriate dosage may be achieved using routine experimentation, byconstructing a matrix of values and testing different points in thematrix, which is all within the ordinary skills of a trained physicianor veterinary.

Pharmaceutically Acceptable Salts

The compound of the invention may be provided in any form suitable forthe intended administration. Suitable forms include pharmaceutically(i.e. physiologically) acceptable salts of the compound of theinvention.

Such pharmaceutically acceptable salts and common methodology forpreparing them are known in the art. Further details may be found in PStahl et al, Handbook of Pharmaceutical Salts: Properties, Selection andUse; Wiley-VCH, 2002.

The chemical compound of the invention may be provided in dissoluble orindissoluble forms together with a pharmaceutically acceptable solventsuch as water, ethanol, and the like. Dissoluble forms may also includehydrated forms such as the monohydrate, the dihydrate, the hemihydrate,the trihydrate, the tetrahydrate, and the like. In general, thedissoluble forms are considered equivalent to indissoluble forms for thepurposes of this invention.

Steric Isomers

It will be appreciated by those skilled in the art that the compounds ofthe present invention may exist in different stereoisomeric forms,including enantiomers, diastereomers or cis-trans-isomers.

The invention includes all such isomers and any mixtures thereofincluding racemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the enantiomeric compounds(including enantiomeric intermediates) is, in the case the compoundbeing a chiral acid, by use of an optically active amine, and liberatingthe diastereomeric, resolved salt by treatment with an acid. Anothermethod for resolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of D- or L- (tartrates, mandelates,or camphorsulphonate) salts for example.

The chemical compounds of the present invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active carboxylicacid such as that derived from (+) or (−) phenylalanine, (+) or (−)phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

N-Oxides

In the context of this invention an N-oxide designates an oxidederivative of a tertiary amine, including a nitrogen atom of an aromaticN-heterocyclic compound, a non-aromatic N-heterocyclic compounds, atrialkylamine and a trialkenylamine.

N-oxides of the compounds of the invention may be prepared by oxidationof the corresponding nitrogen base using a conventional oxidizing agentsuch as hydrogen peroxide in the presence of an acid such as acetic acidat an elevated temperature, or by reaction with a peracid such asperacetic acid in a suitable solvent, e.g. dichloromethane, ethylacetate or methyl acetate, or in chloroform or dichloromethane with3-chloroperoxybenzoic acid.

Labelled Compounds

The compounds of the invention may be used in their labelled orunlabelled form. In the context of this invention the labelled compoundhas one or more atoms replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. The labelling will allow easy quantitative detection of saidcompound.

The labelled compounds of the invention may be useful as diagnostictools, radio tracers, or monitoring agents in various diagnosticmethods, and for in vivo receptor imaging.

The labelled isomer of the invention preferably contains at least oneradionuclide as a label. Positron emitting radionuclides are allcandidates for usage. In the context of this invention the radionuclideis preferably selected from ²H (deuterium), ³H (tritium), ¹¹C, ¹³C, ¹⁴C,¹³¹I, ¹²⁵I, ¹²³I and ¹⁸F.

The physical method for detecting the labelled isomer of the presentinvention may be selected from Position Emission Tomography (PET),Single Photon Imaging Computed Tomography (SPECT), Magnetic ResonanceSpectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed AxialX-ray Tomography (CAT), or combinations thereof.

Deuterated Analogs

The compounds of the invention may be provided in the form of theirdeuterated analogs. Deuterium forms bonds with carbon that vibrate at alower frequency and are thus stronger than C—H bonds. Therefore “heavyhydrogen” (deuterium) versions of drugs may be more stable towardsdegradation and last longer in the living organism.

Methods of Preparation

The chemical compounds of the invention may be prepared by conventionalmethods for chemical synthesis, e.g. those described in the workingexamples. The starting materials for the processes described in thepresent application are known or may readily be prepared by conventionalmethods from commercially available chemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Persons skilled in the art will appreciate that, in order to obtaincompounds of the invention in an alternative, and in some occasions,more convenient manner, the individual process steps mentionedhereinbefore may be performed in a different order, and/or theindividual reactions may be performed at different stage in the overallroute (i.e. chemical transformations may be performed upon differentintermediates to those associated hereinbefore with a particularreaction).

Biological Activity

The compounds according to the present invention possess modulation ofcortical and basal ganglia dopaminergic and N-methyl-D-aspartate (NMDA)receptor-mediated glutamatergic neurotransmission and both they andtheir pharmaceutical compositions are useful in treating numerouscentral nervous system disorders, including both psychiatric andneurological disorders. Particularly, the compounds and theirpharmaceutical compositions may be used in the treatment of CNSdisorders where the dopaminergic and glutamatergic system isdysfunctional due to direct or indirect causes.

The compounds and compositions according to the invention can be used toimprove all forms of psychosis, including schizophrenia andschizophreniform and bipolar disorders as well as drug induced psychoticdisorders. Iatrogenic psychoses and hallucinoses and non-iatrogenicpsychoses and hallucinoses may also be treated.

In a special embodiment the disease, disorder or condition contemplatedaccording to the invention is a form of psychosis, in particularschizophrenia, a schizophreniform disorder, a bipolar disorder, or adrug induced psychotic disorder.

Mood and anxiety disorders, depression and obsessive-compulsive diseasemay also be treated with the compounds and compositions according to theinvention.

Compounds with modulating effects on dopaminergic and glutamatergicsystems may also be used to improve motor and cognitive functions and inthe treatment of emotional disturbances related to ageing,neurodegenerative (e.g. dementia and age-related cognitive impairment)and developmental disorders (such as Autism spectrum disorders, ADHD,Cerebral Palsy, Gilles de la Tourette's syndrome) as well as after braininjury. Such brain injury may be induced by traumatic, inflammatory,infectious, neoplastic, vascular, hypoxic or metabolic causes or bytoxic reactions to exogenous chemicals, wherein the exogenous chemicalsare selected from the group consisting of substances of abuse,pharmaceutical compounds and environmental toxins

The compounds and pharmaceutical compositions according to the inventionmay also be used in behavioural disorders usually first diagnosed ininfancy, childhood, or adolescence as well as in impulse controldisorders.

They can also be used for treating substance abuse disorders as well asdisorders characterized by misuse of food. They are further useful fortreatment of a condition selected from the group consisting of sleepdisorders, sexual disorders, eating disorders, obesitas, and headachesand other pains in conditions characterized by increased muscular tone.

Neurological indications include the use of the compounds and theirpharmaceutical compositions to improve mental and motor function inParkinson's disease, and in related parkinsonian syndromes, dyskinesias(including L-DOPA induced dyskinesias and tardive dyskinesias) anddystonias. They may also be used to ameliorate tics and tremor ofdifferent origins.

They can also be used in the treatment of Huntington's disease and othermovement disorders as well as movement disorders induced by drugs.Restless legs and related disorders as well as narcolepsy may also betreated with compounds included according to the invention.

The compounds and their pharmaceutical compositions according to thepresent invention can be used for the treatment of Alzheimer's diseaseor related dementia disorders.

In a further embodiment the disease, disorder or condition contemplatedaccording to the invention is selected from the group of schizophrenia,L-DOPA induced dyskinesias and Huntington's disease.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof the invention.

While a compound of the invention for use in therapy may be administeredin the form of the raw compound, it is preferred to introduce the activeingredient, optionally in the form of a physiologically acceptable salt,in a pharmaceutical composition together with one or more adjuvants,excipients, carriers, buffers, diluents, and/or other customarypharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers therefore, and,optionally, other therapeutic and/or prophylactic ingredients, know andused in the art. The carrier(s) must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and notharmful to the recipient thereof.

The pharmaceutical composition of the invention may be administered byany convenient route, which suits the desired therapy. Preferred routesof administration include oral administration, in particular in tablet,in capsule, in dragé in powder, or in liquid form, and parenteraladministration, in particular cutaneous, subcutaneous, intramuscular, orintravenous injection. The pharmaceutical composition of the inventioncan be manufactured by the skilled person by use of standard methods andconventional techniques appropriate to the desired formulation. Whendesired, compositions adapted to give sustained release of the activeingredient may be employed.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, bronchial, nasal, pulmonal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof. Such forms includesolids, and in particular tablets, filled capsules, powder and pelletforms, and liquids, in particular aqueous or non-aqueous solutions,suspensions, emulsions, elixirs, and capsules filled with the same, allfor oral use, suppositories for rectal administration, and sterileinjectable solutions for parenteral use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound of the present invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,cellulose, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations, intended for conversionshortly before use to liquid form preparations for oral administration.Such liquid forms include solutions, suspensions, and emulsions. Inaddition to the active component such preparations may comprisecolorants, flavours, stabilisers, buffers, artificial and naturalsweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the chemical compound of theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tra-gacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including in-tranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive in-gredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

In one embodiment, when the pharmaceutical composition of the inventionis intended for treating patients with abuse liability and withdrawalsymptoms caused by nicotine addiction, formulations such as gums,patches, sprays, inhalers, aerosols, etc. are contemplated.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

A therapeutically effective dose refers to that amount of activeingredient, which ameliorates the symptoms or condition. Therapeuticefficacy and toxicity, e.g. ED₅₀ and LD₅₀, may be determined by standardpharmacological procedures in cell cultures or experimental animals. Thedose ratio between therapeutic and toxic effects is the therapeuticindex and may be expressed by the ratio LD₅₀/ED₅₀. Pharmaceuticalcompositions exhibiting large therapeutic indexes are preferred.

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired, and the exact dosage should of course be determined by thepractitioner.

The actual dosage depends on the nature and severity of the diseasebeing treated, the exact mode of administration and form ofadministration, and is within the discretion of the physician, and maybe varied by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

The compounds of the present invention are modulators of cortical andbasal ganglia dopaminergic and N-methyl-D-aspartate (NMDA)receptor-mediated glutamatergic neurotransmission and therefore usefulfor the treatment of a range of ailments involving modulation ofdopaminergic and glutamatergic function.

In another aspect the invention provides a method for the treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disease, disorder orcondition is responsive to modulation of dopaminergic and glutamatergicfunction in the central nervous system, and which method comprisesadministering to such a living animal body, including a human, in needthereof an effective amount of a compound of the invention, astereoisomer or a mixture of its stereoisomers, or a pharmaceuticallyacceptable salt thereof.

The indications contemplated according to the invention are those statedabove.

It is at present contemplated that suitable dosage ranges are 0.1 to1000 milligrams daily, 10-500 milligrams daily, and especially 30-100milligrams daily, dependent as usual upon the exact mode ofadministration, form in which administered, the indication toward whichthe administration is directed, the subject involved and the body weightof the subject involved, and further the preference and experience ofthe physician or veterinarian in charge.

EXAMPLES

The invention is further illustrated in the examples below and asoutlined below in Scheme 1, which in no way are intended to limit thescope of the invention.

The substituents in Scheme 1 are as follows: A is a leaving group, andR², R³, R⁴, R′ and R″ are as defined above.

Example 1 N-[2-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)ETHYL]PROPAN-1-AMINE

A mixture of 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (2.65g, 8.9 mmol) and propan-1-amine (5.24 ml, 63.7 mmol) in ethanol (32 ml)was divided into 3 aliquots which were each heated under microwaveradiation at 120° C. for 30 min. The reaction mixtures were cooled toroom temperature, filtrated and pooled before the volatiles wereevaporated. Purification by flash column chromatography (ethylacetate/methanol, 1:0 to 1:1) gave the title compound (2.14 g, 87%). Theamine was converted to the hydrochloric acid salt and re-crystallizedfrom methanol/diethyl ether: M.p. 191° C. MS m/z (relative intensity, 70eV) 275 (M+, 2), 246 (32), 73 (5), 72 (bp), 56 (11).

Example 2 N-[2-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)ETHYL]BUTAN-1-AMINE

Preparation according to Example 1 but performed in one portion:1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.3 g, 1.01 mmol)and butan-1-amine 0.61 ml, 0.5907 mmol) in ethanol (4 ml). Yield: 290 mg(99%). The amine was converted to the hydrochloric acid salt andre-crystallized from ethanol/diethyl ether: M.p. 204° C. MS m/z(relative intensity, 70 eV) 289 (M+, 1), 246 (35), 86 (bp), 56 (12), 87(12).

Example 3 N-ETHYL-2-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)ETHANAMINE

Preparation according to Example 1 but performed in one portion:1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.321 g, 1.08 mmol)and ethanamine (4.3 ml, 8.6 mmol 2 M in methanol) in ethanol (6 ml).Yield: 255 mg (90%). The amine was converted to the hydrochloric acidsalt and re-crystallized from ethanol/diethyl ether: M.p. 200.8-201.1°C. MS m/z (relative intensity, 70 eV) 261 (M+, 3), 94 (6), 59 (12), 58(bp), 56 (8).

Example 4N-[2-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)ETHYL]-N-METHYL-PROPAN-1-AMINE

A mixture of Example 1 (0.54 g, 1.95 mmol) in formic acid (5.75 ml) andformaldehyde (40% solution, 5.1 ml) was heated at 85° C. for 5 h. Thesolution was allowed to reach ambient temperature, water (5 ml) anddiethyl ether was added, the phases were separated and the aqueous phasewas basified by the addition of aqueous sodium hydroxide (5 M). Theaqueous phase was extracted twice with ethyl acetate, the combinedorganic phases were dried (Na₂SO₄) and evaporated under pressure to givethe crude product which was then purified by flash chromatography(EtOAc:MeOH 100:0 then gradually changed to 0:100. The amine wasconverted to the hydrochloric acid salt and re-crystallized frommethanol/diethyl ether: M.p. 128-130° C. MS m/z (relative intensity, 70eV). 289 (M+, 1), 260 (26), 87 (6), 86 (bp), 58 (6).

Example 5 N-[2-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)ETHYL]BUTAN-2-AMINE

Preparation according to Example 1 but performed in one portion:1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol)and sec-butylamine 1.37 ml, 13.46 mmol) in ethanol (5 ml). Purificationby flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15)gave the title compound (342 mg, 70%). The amine was converted to thehydrochloric acid salt and re-crystallized from methanol/diethyl ether:M.p. 166.5° C. MS m/z (relative intensity, 70 eV) 289 (M+, 1), 261 (25),260 (bp), 86 (49), 70 (12).

Example 6 N-[2-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)ETHYL]CYCLOPENTANAMINE

Preparation according to Example 1 but performed in one portion:1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol)and cyclopentylamine (1.34 ml, 13.46 mmol) in ethanol (5 ml).Purification by flash column chromatography (ethyl acetate/methanol,100:0 to 85:15) gave the title compound (443 mg, 87.4%). The amine wasconverted to the hydrochloric acid salt and re-crystallized frommethanol/diethyl ether: M.p. 207.5° C. MS m/z (relative intensity, 70eV) 301(M+, 2), 272 (7), 99 (24), 98 (bp), 70 (7).

Example 7N-[2-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)ETHYL]-2-METHYL-BUTAN-2-AMINE

Preparation according to Example 1 but performed in one portion:1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol)and tert-amylamine (1.61 ml, 13.46 mmol) in ethanol (5 ml). Purificationby flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15)gave the title compound (389 mg, 76.2%). The amine was converted to thehydrochloric acid salt and re-crystallized from methanol/diethyl ether:M.p. 190.2° C. MS m/z (relative intensity, 70 eV) 303 (M+, 0), 288 (21),276 (10), 275 (41), 274 (bp), 84 (10).

Example 8 N-[2-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)ETHYL]CYCLOBUTANAMINE

Preparation according to Example 1 but performed in one portion:1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol)and cyclobutylamine (1.17 ml, 13.46 mmol) in ethanol (4 ml).Purification by flash column chromatography (ethyl acetate/methanol,100:0 to 85:15) gave the title compound (400 mg, 82.7%). The amine wasconverted to the hydrochloric acid salt and re-crystallized frommethanol/diethyl ether: M.p. 202° C. MS m/z (relative intensity, 70 eV)287 (M+, 0), 260 (33), 259 (91), 216 (bp), 215 (23), 56 (73).

Example 9 N-[2-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)ETHYL]PROPAN-2-AMINE

Preparation according to Example 1 but performed in one portion:1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol)and isopropylamine (1.15 ml, 13.46 mmol) in ethanol (4 ml). Purificationby flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15)gave the title compound (421 mg, 90.9%). The amine was converted to thehydrochloric acid salt and re-crystallized from methanol/diethyl ether:M.p. 173° C. MS m/z (relative intensity, 70 eV) 275 (M+, 4), 261 (16),260 (41), 73 (32), 72 (bp).

Example 10 1-[2-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)ETHYL]PIPERIDINE

Preparation according to Example 1 but performed in one portion:1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol)and piperidine (1.33 ml, 13.46 mmol) in ethanol (5 ml). Purification byflash column chromatography (ethyl acetate/methanol, 100:0 to 85:15)gave the title compound (480 mg, 94.7%). The amine was converted to thehydrochloric acid salt and re-crystallized from methanol/diethyl ether:M.p. 194.6° C. MS m/z (relative intensity, 70 eV) 301(M+, 1), 99 (8), 98(bp), 96 (4), 55 (5).

Example 11 N,N-DIETHYL-2-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)ETHANAMINE

Preparation according to Example 1 but performed in one portion:1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol)and di-ethylamine (1.39 ml, 13.46 mmol) in ethanol (4 ml). Purificationby flash column chromatography (ethyl acetate/methanol, 1:0 to 1:1) gavethe title compound (300 mg, 61.6%). The amine was converted to thehydrochloric acid salt and re-crystallized from methanol/diethyl ether:M.p. 172.3° C. MS m/z (relative intensity, 70 eV) 289 (M+, 1), 274 (6),87 (6), 86 (bp), 58 (5).

Example 12 N-[2-(3-CHLORO-5-METHYLSULFONYL-PHENOXY)ETHYL]PROPAN-1-AMINE

Preparation according to Example 1 but performed in one portion:1-(2-bromoethoxy)-3-chloro-5-methylsulfonyl-benzene (0.5 g, 1.59 mmol)and propane-1-amine (1.04 ml, 12.76 mmol) in ethanol (5 ml). Yield: 368mg (79.1%). The amine was converted to the hydrochloric acid salt andre-crystallized from ethanol/diethyl ether: M.p. 195-197° C. MS m/z(relative intensity, 70 eV) 291 (M+, 1), 264 (8), 262 (22), 73 (9), 72(bp).

Example 13 N-{2-[3-FLUORO-5-(METHYLSULFONYL)PHENOXY]ETHYL}-N-PROPYLAMINED2

2-[3-Fluoro-5-(methylsulfonyl)phenoxy]ethanamine (0.3 g, 1.26 mmol),propyl 4-methylbenzenesulfonate D2 (1.04 ml, 12.76 mmol) and potassiumcarbonate (0.35 g, 2.52 mmol) in acetonitrile (10 ml). The mixture washeated under microwave radiation at 120° C. for 45 min. The reactionmixtures were cooled to room temperature, filtrated and pooled beforethe volatiles were evaporated. Purification by flash columnchromatography (ethyl acetate/methanol, 1:0 to 1:1) gave the titlecompound (0.15 g, 44%). The amine was converted to the hydrochloric acidsalt and re-crystallized from methanol/diethyl ether. MS m/z (relativeintensity, 70 eV) 277 (M+, 2), 248 (26), 138 (3), 94 (3), 74 (bp).

Example 14N-(CYCLOPROPYLMETHYL)-N-{2-[3-FLUORO-5-(METHYLSULFONYL)-PHENOXY]ETHYL}AMINE

Preparation according to Example 1 but performed in one portion:1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.05 g, 0.16 mmol)and aminomethylcyclopropane (0.11 ml, 1.3 mmol) in ethanol (5 ml). MSm/z (relative intensity, 70 eV) 287 (M+, 2), 246 (6), 138 (2), 84 (bp),56 (14).

Example 15N-{2-[3-FLUORO-5-(METHYLSULFONYL)PHENOXY]ETHYL}-N-ISOBUTYLAMINE

Preparation according to Example 1 but performed in one portion:1-(2-bromoethoxy)-3-chloro-5-methylsulfonyl-benzene (0.05 g, 0.16 mmol)and isobutylamine (0.2 ml, 1.3 mmol) in ethanol (5 ml). MS m/z (relativeintensity, 70 eV) 289 (M+, 1), 246 (bp), 138 (2), 86 (70), 56 (17).

Example 16 1-[2-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)ETHYL]AZETIDINE

1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.6 mmol),azetidine (0.23 ml, 3.2 mmol) and potassium carbonate (0.58 g, 4.2 mmol)was dissolved in acetonitrile (10 ml). The mixture was heated in asealed container at 120° C. for 2 h. The reaction mixture was cooled toroom temperature, CH₂Cl₂ (100 ml) was added, solids was filtered off andthe volatiles were evaporated. The amine was converted to the fumaricacid salt and re-crystallized from methanol/diethyl ether. MS m/z(relative intensity, 70 eV) 273 (M+, 1), 94 (5), 82 (3), 71 (5), 70(bp).

Example 17 1-(3-FLUORO-5-METHYLSULFONYL-PHENOXY)-N-PROPYL-PROPAN-2-AMINE

Sodium triacetoxyborohydride (1.16 g, 5.51 mmol) was added to a stirredmixture of 1-(3-fluoro-5-methylsulfonyl-phenoxy)propan-2-one (0.905 g,3.67 mmol), propylamine (0.24 g, 4.04 mmol), acetic acid (0.5 g, 8.33mmol) and molecular sieves (2 g, 4 Å, 4-8 mesh) in dry1,2-dichloroethane (20 ml) the mixture was stirred at ambienttemperature for 24 h, the suspension was filtrated and sodium carbonate(100 ml, 10% aqueous solution) was added. The aqueous phase wasextracted with dichloromethane (3×50 ml). The combined organic phase wasdried with Na₂SO₄ and evaporated. Purification on flash chromatography(ethyl acetate:methanol 1:0 to 4:1). 0.3 g, 28%. MS m/z (relativeintensity, 70 eV) 289 (M+, 1), 260 (9), 152 (4), 87 (6), 86 (bp).

Example 18 2-(3-fluoro-5-methylsulfonyl-phenoxy)-N-propyl-propan-1-amine

Toluenesulfonyl chloride (0.60 g, 3.1 mmol) was added to a stirredmixture of 4-dimethylaminopyridine (0.41 g, 3.4 mmol), triethylamine(0.53 g, 5.26 mmol) and a mixture of1-(3-fluoro-5-methylsulfonyl-phenoxy)propan-2-ol and2-(3-fluoro-5-methylsulfonyl-phenoxy)propan-1-ol (0.65 g, 2.63 mmol) indry dichloromethane (20 ml). The resulting mixture was stirred atambient temperature for 5 h, HCl (100 ml, 5% aqueous solution) wasadded, the aqueous phase was extracted with dichloro-methane (2×50 ml),the combined organic phase was washed with Brine (50 ml) and sodiumcarbonate (50 ml, 5% aqueous solution).

The resulting oil was dissolved in ethanol (5 ml) and methanol (5 ml)and propylamine (3.24 ml, 39.51 mmol) was added, the resulting mixturewas heated to reflux for 15 h. The crude mixture was concentrated undervacuum and purified on flash chromatography (ethyl acetate:methanol 1:0to 5:1). 0.52 g (as a mixture of2-(3-fluoro-5-methylsulfonyl-phenoxy)-N-propyl-propan-1-amine and1-(3-fluoro-5-methylsulfonyl-phenoxy)-N-propyl-propan-2-amine), 68%. MSm/z (relative intensity, 70 eV) 289 (M+, 1), 260 (3), 73 (5), 72 (bp),70 (9).

Preparations Preparation 13-FLUORO-5-METHYLSULFONYL-PHENOL

Nitrogen was bubbled through a solution of 3-bromo-5-fluorophenol (10 g,51.31 mmol) in dry dimethyl sulfoxide (70 ml) for 10 min after whichsodium methanesulfinate (8.27 g, 76.96 mmol), cupper(I)iodide (5.86 g,30.79 mmol), L-proline (7.09 g, 61.57 mmol) and potassium carbonate(4.25 g, 30.79 mmol) was added. The nitrogen flow was continued for anadditional 10 min after which the mixture was heated at 100° C. for 24h. Ethyl acetate (100 ml) and water (100 ml) was added and the phaseswere separated. The aqueous phase was extracted with ethyl acetate(2×100 ml), the combined organic phase was washed with aqueous lithiumchloride (100 ml, 5%) and aqueous hydrochloric acid (100 ml, 5%), dried(Na₂SO₄) and evaporated. Purification by flash column chromatography(ethyl acetate/isooctane, 0:1 to 1:1) gave the title compound (7.17 g,73%). MS m/z (relative intensity, 70 eV) 190 (M+, 81), 175 (27), 128(50), 111 (bp), 83 (58).

Preparation 2 1-(2-BROMOETHOXY)-3-FLUORO-5-METHYLSULFONYL-BENZENE

A mixture of 3-fluoro-5-methylsulfonyl-phenol (4.2 g, 22.08 mmol),1.2-dibromoethane (24 ml, 27.7 mmol) and potassium carbonate (6.1 g,44.2 mmol) in acetonitrile (36 ml) was divided into 6 aliquots whichwere each heated under microwave radiation at 120° C. for 30 min. Thereaction mixtures were cooled to room temperature, filtrated and pooled.The volatiles were evaporated, aqueous sodium carbonate (100 ml, 10%)was added and the mixture was extracted with ethyl acetate (2×100 ml).The combined organic phase was washed with brine (75 ml), dried (Na₂SO₄)and evaporated. Purification by flash column chromatography (ethylacetate/isooctane, 0:1 to 1:0) gave the title compound (4.77 g, 73%). MSm/z (relative intensity, 70 eV 298 (M+, 18), 296 (M+, 18), 109 (bp), 107(99), 82 (15).

Preparation 3 TERT-BUTYL2-[3-FLUORO-5-(METHYLSULFONYL)PHENOXY]ETHYL-CARBAMATE

A mixture of triphenylphosphine (1.9 g, 7.3 mmol) in dry THF (20 ml) wasflushed with N₂(g) and DEAD (3.1 ml, 6.9 mmol) was added drop-wise,1.2-dibromoethane followed by 3-fluoro-5-methylsulfonyl-phenol (1.1 g,6.1 mmol) and then boc-glycinol (1.0 ml, 6.1 mmol) in portions. Themixture was stirred at 70° C. for 20 h, cooled to room temperature andwater and EtOAc was added. The aqueous phase was extracted with ethylacetate (2×100 ml). The combined organic phase was washed with aqueousNaOH (3 M, 50 ml) and brine (75 ml), dried (Na₂SO₄) and evaporated.Purification by flash column chromatography (ethyl acetate/isooctane,0:1 to 1:0) gave the title compound (1.4 g, 70%). MS m/z (relativeintensity, 70 eV 298 (M+, 18), 296 (M+, 18), 109 (bp), 107 (99), 82(15).

Preparation 4 2-[3-FLUORO-5-(METHYLSULFONYL)PHENOXY]ETHANAMINE

A mixture of tert-butyl2-[3-fluoro-5-(methylsulfonyl)phenoxy]ethyl-carbamate (1.4 g, 4.2 mmol)in EtOH (18 ml) was added HCl (1.25 M in EtOH, 6 ml). The mixture wasstirred at ambient temperature for 20 h. The aqueous phase was madebasic by addition of aqueous NaOH (1 M, 50 ml) and extracted with ethylacetate (2×100 ml). The combined organic phase was washed with brine (75ml), dried (Na₂SO₄) and evaporated to yield the title compound (0.77 g,77%). MS m/z (relative intensity, 70 eV 298 (M+, 18), 296 (M+, 18), 109(bp), 107 (99), 82 (15).

Preparation 5 3-CHLORO-5-METHYLSULFONYL-PHENOL

Preparation according to Preparation 1: 3-bromo-5-chlorophenol (4.0 g,19.3 mmol), sodium methanesulfinate (3.1 g, 28.9 mmol), cupper(I)iodide(2.2 g, 11.5 mmol), L-proline (2.7 g, 23.1 mmol), potassium carbonate(1.6 g, 11.6 mmol), dry dimethyl sulfoxide (70 ml). Yield: 3.7 g (92%).MS m/z (relative intensity, 70 eV) 206 (M+, 88), 191 (36), 144 (58), 127(bp), 99 (76).

Preparation 6 1-(2-BROMOETHOXY)-3-CHLORO-5-METHYLSULFONYL-BENZENE

Preparation according to Preparation 2: 3-chloro-5-methylsulfonyl-phenol(2.8 g, 13.5 mmol), 1.2-dibromoethane (12 ml, 135 mmol), potassiumcarbonate (3.7 g, 27.1 mmol), acetonitrile (15 ml) Yield: 2.1 g, 50%).MS m/z (relative intensity, 70 eV 314 (M+, 35), 312 (M+, 25), 206 (7),126 (9), 109 (98), 107 (bp).

Preparation 7 2-(3-fluoro-5-methylsulfonyl-phenoxy)propan-1-ol

A mixture of 1-bromo-2-propanol (70%) and 2-bromo-1-propanol (30%) (5.81g, 41.8 mmol) was added to a solution of3-fluoro-5-methylsulfonyl-phenol (1.59 g, 8.36 mmol) and potassiumcarbonate (2.37 g, 16.71 mmol) in dry dimethyl formamide (10 ml), themixture was heated to 120° C. for 20 hours, the mixture was allowed tocool to ambient temperature and water (100 ml) was added. The aqueousphase was extracted with ethyl acetate (3×100 ml), the combined organicphase was washed with LiCl (5% aqueous solution, 4×50 ml), brine (50 ml)and dried with Na₂SO₄ and evaporated. Purification flash chromatography(isooctane:ethyl acetate 1:0 to 3:2). 0.65 g (mixture of1-(3-fluoro-5-methylsulfonyl-phenoxy)propan-2-ol and2-(3-fluoro-5-methylsulfonyl-phenoxy)propan-1-ol), 31%. MS m/z (relativeintensity, 70 eV) 248 (M+, 14), 204 (54), 203 (bp), 191 (37), 190 (44).

Preparation 8 1-(3-fluoro-5-methylsulfonyl-phenoxy)propan-2-one

1-Chloroacetone (95%, 2.66 g, 27.34 mmol) was added to a stirredsolution of 3-fluoro-5-methylsulfonyl-phenol (80%, 1.3 g, 5.46 mmol) andpotassium carbonate (2.26 g, 16.40 mmol) in dry dimethyl formamide (10ml), the mixture was heated to 120° C. for 20 minutes, the mixture wasallowed to cool to ambient temperature and water (100 ml) was added. Theaqueous phase was extracted with ethyl acetate (3×100 ml), the combinedorganic phase was washed with LiCl (5% aqueous solution, 4×50 ml), brine(50 ml) and dried with Na₂SO₄ and evaporated. Purification on flashchromatography (isooctane:ethyl acetate 1:0 to 3:2). 0.905 g, 67%. MSm/z (relative intensity, 70 eV) 246 (M+, 79), 204 (55), 203 (bp), 141(30), 94 (67).

Biological Activity 3,4-dihydroxyphenyl-acetic acid (DOPAC) in thestriatum

The increased turnover of dopamine in the terminal areas of theascending dopaminergic projections of the mammalian brain can beillustrated by measuring of changes in biochemical indices in the brainwith the characteristic features of dopamine antagonists, e.g. producingincreases in concentrations of dopamine metabolites such as3,4-dihydroxyphenyl-acetic acid (DOPAC) in the striatum.

Test results are shown in Table 1.

TABLE 1 Estimated ED₅₀ values on increase of DOPAC(3,4-dihydroxyphenylacetic acid) in the rat striatum after systemicadministration of test compound. For methods and statisticalcalculations see the below test methods. ED₅₀ DOPAC Compound (μmol/kg)Example 1   8.5  (7.4-10.3) Example 2   4.2 (3.5-5.3) Example 4  28.1(24.5-28.1) Example 8  36 (25.6-51.1) Example 10 14.5 (10.8-16.9)Example 12 10.5  (7.7-15.6)

Effects on Spontaneous Locomotion

Prior art dopamine receptor antagonists are known to induce profounddecrease in locomotor activity (catalepsy). Effects of a compound of theinvention on spontaneous locomotion are shown in Table 2.

TABLE 2 Effects of a compound of the invention on Locomotor activity indrug-naive rats. The animals were placed in the motility metersimmediately after drug administration and locomotor activity wasrecorded for 60 minutes (counts/60 min ± SEM). Compound Control group3.7 μmol/kg 11 μmol/kg 33 μmol/kg Example 1  6414 8049 7325 6025 Example2  14161 13941 8617 6325 Example 4  13890 11435 10025 12829 Example 8 13633 10319 12888 12872 Example 10 9816 11979 9344 8144 Example 12 1363014414 12740 7826

Amphetamine-Induced Hyper-Locomotion

The increase in activity after treatment with d-amphetamine is astandard model of hyperdopaminergia. In this model, dopaminergicneurotransmission is increased by systemic administration ofd-amphetamine at a dose that is sufficiently high to produce a largeincrease in locomotor activity. The ability of a compound to antagonizethis hyperactivity reflects anti-dopaminergic properties. Furthermore,antagonism of d-amphetamine induced hyperactivity is widely used as astandard assay of antipsychotic activity (see Psychopharmacology 4thGeneration of progress Chapter 68, p 793-795).

The effects of a compound of the invention on the increase in activityinduced by direct or indirect dopaminergic agonists, i.e. d-amphetamineand congeners are shown in Table 3.

TABLE 3 Effect of compound of the present invention on reduction ofamphetamine-induced hyper-locomotion. For methods and statisticalcalculations see the below test methods. ED₅₀ Compound μmol/kg Example 124 (18-30) Example 4 69  (24-290)

Reduction of MK-801-Induced Hyper-Locomotion Another animal model ofantipsychotic activity is based on administration of the glutamateantagonist MK-801. Glutamate antagonists (i.e. NMDA antagonists), caninduce psychoses in man (see Psychopharmacology, 4th Generation ofprogress Chapter 101, p. 1205 and 1207) and induce behaviouralaberrations in animals. Thus, the ability of a drug to affectschizophrenia and psychotic states can be measured using behaviouralmodels based on experimentally-induced hypoglutamatergic states. In thisstudy the NMDA antagonist MK-801 (0.7 mg/kg i.p.) was used to create ahypoglutamatergic state where the rats display abnormal, hyperactivebehaviour.

Test results for a compound of the present invention are seen in Table4.

TABLE 4 Effect of compound of the present invention on reduction ofMK-801-induced hyper-locomotion (0.7 mg/kg i.p. 90 minutes before testcompound). For methods and statistical calculations see the below testmethods. The animals were placed in the motility meters immediatelyafter test compound administration and locomotor activity was recordedbetween 45 and 60 minutes after administration (counts/15 min ± SEM)ED₅₀ Compound μmol/kg Example 1 5.6 (0.3-18)  Example 8 40  (20-100)

Increase of Arc Gene Expression

It is known that the dopaminergic systems of the brain interact stronglywith other transmitter systems (see Psychopharmacology, 4th Generationof progress, Chapter 101, pages 1208-1209).

To investigate potential effects of compounds of the present inventionon cortical and striatal NMDA receptor related synaptic signalling, ArcmRNA induction was assessed upon acute administration of a compound ofthe present invention. Arc (Arc/Arg3.1-activity regulatedcytoskeleton-associated protein/activity-regulated gene 3.1; (Link W etal.; Proc Natl Acad Sci USA 1995 92 5734-5738; Lyford G L et al; Neuron1995 14 433-445)), is an immediate early gene (IEG), induced by synapticactivity, whose expression and localization at synaptic sites istriggered specifically by NMDA receptor activation and strongly relatedto neural plasticity (Steward 0, Worley P F; Neuron 2001 30 227-240;Takashi Kawashima et al.; PNAS 2009 106 (1) 316-321; Clive R. Bramham etal.; Exp. Brain Res. 2010 200 125-140).

Test results for a compound of the invention are shown in Table 5.

TABLE 5 Estimated ED₅₀ values on increase of Arc gene expression in therat striatum and cortex after systemic administration of test compound.For methods and statistical calculations see the below test methods.Compound ED₅₀ Arc (μmol/kg) Example 1   13 (striatum) (5.6-77)  Example1 <11 (Cortex)

Test Methods

The following tests are used for evaluation of the compounds accordingto the invention.

In Vivo Test: Behaviour

Behavioural activity is measured using eight Digiscan activity monitors(RXYZM (16) TAO, Omnitech Electronics, Columbus, Ohio, USA), connectedto an Omnitech Digiscan analyzer and an Apple Macintosh computerequipped with a digital interface board (NB DIO-24, NationalInstruments, USA). Each activity monitor consists of a quadratic metalframe (W×L=40 cm×40 cm) equipped with photobeam sensors. Duringmeasurements of behavioural activity, a rat is put in a transparentacrylic cage (WxLxH, 40×40×30 cm) which in turn is placed in theactivity monitor. Each activity monitor is equipped with three rows ofinfrared photobeam sensors, each row consisting of 16 sensors. Two rowsare placed along the front and the side of the floor of the cage, at a90° angle, and the third row is placed 10 cm above the floor to measurevertical activity. Photobeam sensors are spaced 2.5 cm apart. Eachactivity monitor is fitted in an identical sound and light attenuatingbox containing a weak house light and a fan.

The computer software is written using object oriented programming(LabVIEW®, National instruments, Austin, Tex., USA).

Behavioural data from each activity monitor, representing the position(horizontal center of gravity and vertical activity) of the animal ateach time, are recorded at a sampling frequency of 25 Hz and collectedusing a custom written LABView™ application. The data from eachrecording session are stored and analyzed with respect to distancetraveled. Each behavioural recording session lasts 60 min, startingapproximately 4 min after the injection of test compound. Similarbehavioural recording procedures are applied for drug-naïve and drugpre-treated rats. Rats pre-treated with d-amphetamine are given a doseof 1.5 mg/kg i.p. 10 min before the recording session in the activitymonitor. Rats pre-treated with MK-801 are given a dose of 0.7 mg/kg i.p.90 min before the recording session in the activity monitor. The resultsare presented as counts/60 minutes, or counts/30 minutes, in arbitrarylength units. Statistical comparisons are carried out using Student'st-test against the control group. In MK-801 or amphetamine pre-treatedanimals, statistical comparisons are made against the MK801 ord-amphetamine controls, respectively.

ED₅₀ value for reduction of amphetamine-induced hyper-locomotion iscalculated by curve fitting. The evaluation is based on 16 amphetaminepre-treated animals over the dose range 0, 11, 33 and 100 μmol/kg s.c.in one single experiment. Calculations are based on distance during thelast 45 minutes of one hour of measurement. The distances are normalisedto amphetamine-control and fitted by least square minimization to thefunction “End-(End-Control)/(1+(dose/ED₅₀)^(slope))”. The fourparameters (Control, End, ED₅₀ and Slope) are fitted with therestrictions: ED₅₀>0, 0.5<Slope<3, End=0% of control. The restrictionwith locked End is made to focus on potency rather than efficacy. Toestimate confidence levels for the parameters, the fit is repeated 100times with a random evenly distributed squared weight (0 to 1) for everymeasurement value. Presented ED₅₀-ranges cover 95% of these values.

ED₅₀ value for reduction of MK-801-induced hyper-locomotion iscalculated by curve fitting. The evaluation is based on 16 MK-801pre-treated animals over the dose range 0, 11, 33 and 100 μmol/kg s.c.in one single experiment. Calculations are based on distance during thelast 15 minutes of one hour of measurement. The distances are normalisedto MK-801-control and fitted by least square minimization to thefunction “End-(End-Control)/(1+(dose/ED₅₀)^(Slope))”. The fourparameters (Control, End, ED₅₀ and Slope) are fitted with therestrictions: ED₅₀>0, 0.5<Slope<3, End=0% of control. The restrictionwith locked End is made to focus on potency rather than efficacy. Toestimate confidence levels for the parameters, the fit is repeated 100times with a random evenly distributed squared weight (0 to 1) for everymeasurement value. Presented ED₅₀-ranges cover 95% of these values.

In Vivo Test: Neurochemistry

After the behavioural activity sessions, the rats are decapitated andtheir brains rapidly taken out and put on an ice-cold petri-dish. Thelimbic forebrain, the striatum, the frontal cortex and the remaininghemispheral parts of each rat are dissected and frozen. Each brain partis subsequently analyzed with respect to its content of monoamines andtheir metabolites.

The monoamine transmitter substances (NA (noradrenaline), DA (dopamine),5-HT (serotonin)) as well as their amine (NM (normethanephrine), 3-MT(3-methoxytyramine)) and acid (DOPAC (3,4-dihydroxyphenylacetic acid),5-HIAA (5-hydroxyindoleacetic acid), HVA (homovanillic acid))metabolites are quantified in brain tissue homogenates by HPLCseparations and electrochemical detection

The analytical method is based on two chromatographic separationsdedicated for amines or acids. Two chromatographic systems share acommon auto injector with a 10-port valve and two sample loops forsimultaneous injection on the two systems. Both systems are equippedwith a reverse phase column (Luna C18(2), dp 3 μm, 50×2 mm i.d.,Phenomenex) and electrochemical detection is accomplished at twopotentials on glassy carbon electrodes (MF-1000, Bioanalytical Systems,Inc.). The column effluent is passed via a T-connection to the detectioncell or to a waste outlet. This is accomplished by two solenoid valves,which block either the waste or detector outlet. By preventing thechromatographic front from reaching the detector, better detectionconditions are achieved. The aqueous mobile phase (0.4 ml/min) for theacid system contains citric acid 14 mM, sodium citrate 10 mM, MeOH 15%(v/v) and EDTA 0.1 mM. Detection potentials relative to Ag/AgClreference are 0.45 and 0.60V. The aqueous ion pairing mobile phase (0.5ml/min) for the amine system contains citric acid 5 mM, sodium citrate10 mM, MeOH 9%(v/v), MeCN 10.5% v/v), decane sulfonic acid 0.45 mM, andEDTA 0.1 mM. Detection potentials relative to Ag/AgCl reference are 0.45and 0.65V.

ED₅₀ value for the increase of DOPAC in striatum is calculated by curvefitting. The evaluation is based on 40 animals over the dose range 0,3.7, 11, 33 and 100 μmol/kg s.c. in two combined experiments. The DOPAClevels are normalised to control and fitted by least square minimizationto the function “End-(End-Control)/(1+(dose/ED₅₀)^(slope))”. The fourparameters (Control, End, ED₅₀ and Slope) are fitted with therestrictions: ED₅₀>0, 0.5<Slope<3, 350<End<400% of control. To estimateconfidence levels for the parameters, the fit is repeated 100 times witha random evenly distributed squared weight (0 to 1) for everymeasurement value. Presented ED₅₀-ranges cover 95% of these values.

In Vivo Test: Oral Bioavailability

Experiments are performed 24 hours after implantation of arterial andvenous catheters. Test compound is administered orally at 12.5 μmol/kgor intravenously at 5 μmol/kg using the venous catheters, n=3 per group.Arterial blood samples are then taken during six hours at 0, 3, 9, 27,60, 120, 180, 240, 300 and, 360 minutes after administration of the testcompound. The oral bioavailability is calculated as the ratio of the AUC(Area under curve) obtained after oral administration over the AUCobtained after intravenous administration for each rat. The parameterAUC is calculated according to the following:

AUC: the area under the plasma concentration versus time curve from timezero to the last concentration measured (Clast), calculated by thelog/linear trapezoidal method.

The levels of test compound are measured by means of liquidchromatography-mass spectrometry (LC-MS) (Hewlett-Packard 1100MSDSeries). The LC-MS module includes a quaternary pump system, vacuumdegasser, thermostatted autosampler, thermostatted column compartment,diode array detector and API-ES spray chamber. Data handling wasperformed with a HP ChemStation rev.A.06.03. system. Instrumentsettings:MSD mode: Selected ion monitoring (SIM) MSD polarity: PositivGas temp: 350° C. Drying gas: 13.0 l/min Nebulizer gas: 50 psigCapillary voltage: 5000 V Fragmentor voltage: 70 V.

Analytical column: Zorbax eclipse XDB-C8 (4.6×150 mm, 5 μm) at 20° C.The mobile phase is acetic acid (0.03%) (solvent A) and acetonitrile(solvent B). The flow rate of the mobile phase is 0.8 ml/min. Theelution is starting at 12% of solvent B isocratic for 4.5 min, thenincreasing linearity to 60% over 4.5 min.

Extractions procedure: Plasma samples (0.25-0.5 ml) are diluted withwater to 1 ml, and 60 pmol (100 μl) internal standard (−)-OSU6241 isadded. The pH was adjusted to 11 by the addition of 25 μl saturatedNa₂CO₃. After mixing, the samples are extracted with 4 mldichloromethane by shaking for 20 min. The organic layer is aftercentrifugation transferred to a smaller tube and evaporated to drynessunder a stream of nitrogen. The residue is then dissolved in 120 μlmobile phase (acetic acid (0.03%):acetonitrile, 95:5) for LC-MS analysis(10 μl injected). The selective ion (MH⁺) is monitored for each example,and MH⁺296 for (−)-OSU6241((3-[3-(ethylsulfonyl)phenyl]-1-propylpiperidine).

A standard curve over the range of 1-500 pmol is prepared by addingappropriate amounts of test compound to blank plasma samples.

In Vitro Test: Metabolic Stability in Rat Liver Microsomes

Rat liver microsomes are isolated as described by Förlin [Förlin L: ToxAppl Pharm. 54 (3) 420-430, 1980] with minor modifications e.g. 3 ml/gliver of a 0.1 M Na/K*PO₄ buffer with 0.15M KCl, pH 7.4, (buffer 1) isadded before homogenisation, the homogenate is centrifuged for 20minutes instead of 15, the supernatant is ultracentrifuged at 100.000 ginstead of 105.000 g and the pellet from the ultracentrifugation isresuspended in 1 ml/g liver of 20% v/v 87% glycerol in buffer 1.

1 μL of, 0.2 or 1 mM test substance diluted in water, and 10 μL 20 mg/mlrat liver microsome are mixed with 149 μL 37° C. buffer 1 and thereaction is started by addition of 40 μL 4.1 mg/ml NADPH. After 0 or 15minutes incubation at 37° C. in a heating block (LAB-LINE, MULTI-BLOKHeater or lab4you, TS-100 Thermo shaker at 700 rpm) the reaction isstopped by addition of 100 μL pure acetonitrile. The proteinprecipitation is then removed by rejecting the pellet aftercentrifugation at 10.000 g for 10 minutes (Heraeus, Biofuge fresco) in4° C. The test compound is analysed using HPLC-MS (Hewlett-Packard1100MSD Series) with a Zorbax SB-C18 column (2.1×150 mm, 5 μm) using0.03% formic acid and acetonitrile as mobile phase (gradient) or aZorbax Eclipse XDB-C18 (3×75 mm, 3.5 μm) using 0.03% acetic acid andacetonitrile as mobile phase (gradient). The min turnover is calculatedas the fraction of test compound eliminated after 15 minutes, expressedin percent of 0 min levels, i.e. 100×[conc test compound at 0min-concentration at 15 min]/conc at 0 min.

Preparation of liver microsomes is performed as described in Förlin[Förlin L: Tox Appl Pharm. 54, (3) 420-430, 1980]. Protocols forincubation with liver microsomes are referred in Crespi et Stresser[Crespi C L, D M Stressser J. Pharm. Tox. Meth. 44 325-331, 2000], andRenwick et al [Renwick A B et al.; Xenobiotica 2001 31 (4) 187-204].

Microdialysis

Male Sprague-Dawley rats weighing 220-320 g are used throughout theexperiments. Before the experiment the animals are group housed, fiveanimals in each cage, with free access to water and food. The animalsare housed at least one week after arrival prior to surgery and use inthe experiments. Each rat is used only once for microdialysis.

We use a modified version of Waters et al. [Waters et al.; J. Neural.Transm. Gen. Sect. 1994 98 (1) 39-55] of the 1-shaped probe as decribedby Santiago and Westerink [Santiago M, Westerink BHC;Naunyn-Schmiedeberg's Arch. Pharmacol. 1990 342 407-414]. The dialysismembrane we use is the AN69 polyacrylonitrile/sodiummethalylsulfonatecopolymer (HOSPAL; o.d./i.d. 310/220 μm: Gambro, Lund, Sweden). In thedorsal striatum we use probes with an exposed length of 3 mm of dialysismembrane and in the prefrontal cortex the corresponding length is 2.5mm. The rats are operated under isoflurane inhalationanesthesia whilemounted into a Kopf stereotaxic instrument. Coordinates are calculatedrelative to bregma; dorsal striatum AP +1, ML ±2.6, DV −6.3; Pf cortex,AP +3.2, 8° ML ±1.2, DV −4.0 according to Paxinos and Watson [Paxinos G,Watson C: The Rat Brain in Stereotaxic Coordinates; New York, AcademicPress 1986]. The dialysis probe is positioned in a burr hole understereotaxic guidance and cemented with phosphatine dental cement.

The rats are housed individually in cages for 48 h before the dialysisexperiments, allowing them to recover from surgery and minimizing therisk of drug interactions with the anaesthetic during the followingexperiments. During this period the rats have free access to food andwater. On the day of experiment the rats are connected to a microperfusion pump via a swiwel and are replaced in the cage where they canmove freely within its confinements. The perfusion medium is a Ringer'ssolution containing in mmol/l: NaCl; 140, CaCl₂; 1.2, KCl; 3.0, MgCl₂;1.0 and ascorbic acid; 0.04 according to Moghaddam and Bunney [MoghaddamB, Bunney B S; J. Neurochem. 1989 53 652-654]. The pump is set to aperfusion speed of 2 μl/min and 40 μl samples are collected every 20min.

Each sample is analyzed at two HPLC systems. On an autoinjector (CMA200) with a 10-port valve (Valco C10WE), holding two sample loops inseries (4 μl and 20 μl), each brain dialysate sample is loaded in bothloops simultaneously. At injection the 20 μl sample is introduced into acolumn switching system (reverse-phase combined with reverse-phaseion-pairing) for dopamine (DA), noradrenaline (NA), normetanephrine(NM), 3-methoxytyramine (3-MT) and serotonin (5-hydroxytryptamine, 5-HT)determination, while the 4 μl sample is introduced on a reverse-phasecolumn for the chromatography of the acidic monoamine metabolites3,4-di-hydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and5-hydroxyindoleacetic acid (5-HIAA). The currents generated by the twoEC detectors are converted to digital data and evaluated usingChromeleon software (Dionex) on a PC. The method sample turn over timeis 4.5 min and two parallel experiments are normally analyzedsimultaneously on the system. After the experiment the rats areuncoupled from the perfusion pump and decapitated. Their brains arerapidly taken out and fixed in Neo-fix solution (Kebo-lab, Sweden) forsubsequent inspection of probe localisation. The Animal Ethics Committeein Göteborg, Sweden approved the procedures applied in theseexperiments.

PCR

Total RNA is prepared by the guanidin isothiocyanate method reported byChomczynski & Sacchi [Chomczynski P & Sacchi N; Anal. Biochem. 1987 162156-159]. RNA pellets are solved in MQ water and stored at −80° C. Thesample concentration was determined spectrophotometrically by a NanoDropND-1000. A quality indicator number and an integrity number of r-RNAwere measured with an Experion (Bio-Rad) on random samples.

Reversed transcription was performed by using a SuperScript III kit(Invitrogen). 1 μg of total RNA was reverse transcribed with 5 μl 2×RTReaction Mix, 1 μl RT Enzyme Mix, volume adjusted to 10 μl withDEPC-treated water. 1U of E. coli RNase H was added. cDNA was diluted 40times and stored at −20° C.

For real-time PCR measurements, 0.7 μl of the cDNA reaction wasamplified in a 25 μl reaction mixture containing 1×PCR buffer, 0.2 mMdNTP, 3.7 mM MgCl₂, 0.15 mM SYBR green, 0.4 μM of each primer, and 1UJumpStart Taq DNA polymerase. Real-time PCR was measured on CFX96(Biorad) using the following settings for all genes, 60 s pre-incubationat 95° C., followed by 40 cycles of denaturation at 95° C. for 10 s,annealing at 56° C. for 10 s, and elongation at 72° C. for 10 s.

The primer sequences were as follows:

Hypoxanthine phosphoribosyl transferase (HPRT) Accession Number AF001282) Sense: (SEQ ID NO: 1)5′-GGC CAG ACT TGT TGG ATT TG-3′ Antisense: (SEQ ID NO: 2)5′-CCG CTG TCT TTT AGG CTT TG-3′ Cyclophilin A (Accession Number M19533)Sense: (SEQ ID NO: 3) 5′-GTC TCT TTT CGC CGC TTG CT-3′ Antisense:(SEQ ID NO: 4) 5′-TCT GCT GTC TTT GGA ACT TTG TCT G-3′Activity-regulated gene (Arc) (Accession Number U19866) Sense:(SEQ ID NO: 5) 5′-GTC CCA GAT CCA GAA CCA CA-3′ Antisense:(SEQ ID NO: 6) 5′-CCT CCT CAG CGT CCA CAT AC-3′

Initial DNA amounts were quantified by a standard curve constructed forevery gene using 6 serial 4-fold dilutions of purified PCR products.Correct PCR products were confirmed by agarose gel electroforesis (2%)PCR products were purified with PCR purification kit from Qiagen(Valencia, Calif., USA) All genes were sequenced at MWG, Germany, androutinely by melting curve analysis.

Arc gene amounts were normalised using the geometric mean of the amountsof the two house-keeping genes assessed (HPRT and cyclophilin A).

ED₅₀ value for the increase of Arc in striatum is calculated by curvefitting. The evaluation is based on 20 animals over the dose range 0,11, 33 and 100 μmol/kg s.c. in a single experiments. The Arc levels arenormalised to control and fitted by least square minimization to thefunction “End-(End-Control)/(1+(dose/ED₅₀)^(Slope))”. The fourparameters (Control, End, ED₅₀ and Slope) are fitted with therestrictions: ED₅₀>0, 0.5<Slope<3, 300<End<600% of control. To estimateconfidence levels for the parameters, the fit is repeated 100 times witha random evenly distributed squared weight (0 to 1) for everymeasurement value. Presented ED₅₀-ranges cover 95% of these values.

ED₅₀ value for the increase of Arc in (prefrontal) cortex is evaluatedto be clearly below the lowest dose.

1. A phenoxy-ethyl-amine derivative, wherein the phenoxy-ethyl-aminederivative isN-[2-(3-fluoro-5-methylsulfonyl-phenoxy)ethyl]propan-1-amine, or apharmaceutically acceptable salt thereof.
 2. The phenoxy-ethyl-aminederivative of claim 1, wherein the phenoxy-ethyl-amine derivative is ahydrochloric acid salt ofN-[2-(3-fluoro-5-methylsulfonyl-phenoxy)ethyl]propan-1-amine.
 3. Apharmaceutical composition comprising a therapeutically effective amountof the phenoxy-ethyl-amine derivative of claim 1, or a pharmaceuticallyacceptable salt thereof, together with at least one pharmaceuticallyacceptable carrier, excipient, or diluent.
 4. A method of treatment of adisease or a disorder or a condition of a patient, which disorder,disease or condition is selected from the group consisting of psychosis,schizophrenia, schizophreniform disorder, bipolar disorder, anxietydisorder, depression, obsessive-compulsive disease, dementia,age-related cognitive impairment, Autism spectrum disorders, attentiondeficit hyperactivity disorder (ADHD), Gilles de la Tourette's syndrome,eating disorder, Parkinson's disease, parkinsonian syndrome,L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia, Tardivedyskinesia, dystonia, Huntington's disease, and Alzheimer's disease,which method comprises the step of administering to such as patient inneed thereof a therapeutically effective amount of thephenoxy-ethyl-amine derivative of claim 1, or a pharmaceuticallyacceptable salt thereof.
 5. The method of claim 4, wherein the diseaseor the disorder or the condition is selected from the group consistingof schizophrenia, L-DOPA induced dyskinesia, and Huntington's disease.6. The method of claim 4, wherein the disease or the disorder or thecondition is L-DOPA induced dyskinesia.
 7. A method of treatment ofpsychotic disorder of a patient, which method comprises the step ofadministering to such a patient in need thereof a therapeuticallyeffective amount of the phenoxy-ethyl-amine derivative of claim 1, or apharmaceutically acceptable salt thereof.
 8. A phenoxy-ethyl-aminederivative, wherein the phenoxy-ethyl-amine derivative isN-[2-(3-fluoro-5-methylsulfonyl-phenoxy)ethyl]butan-1-amine, or apharmaceutically acceptable salt thereof.
 9. The phenoxy-ethyl-aminederivative of claim 8, wherein the phenoxy-ethyl-amine derivative is ahydrochloric acid salt ofN-[2-(3-fluoro-5-methylsulfonyl-phenoxy)ethyl]butan-1-amine.
 10. Apharmaceutical composition comprising a therapeutically effective amountof the phenoxy-ethyl-amine derivative of claim 8, or a pharmaceuticallyacceptable salt thereof, together with at least one pharmaceuticallyacceptable carrier, excipient, or diluent.
 11. A method of treatment ofa disease or a disorder or a condition of a patient, which disorder,disease or condition is selected from the group consisting of psychosis,schizophrenia, schizophreniform disorder, bipolar disorder, anxietydisorder, depression, obsessive-compulsive disease, dementia,age-related cognitive impairment, Autism spectrum disorders, ADHD,Gilles de la Tourette's syndrome, eating disorder, Parkinson's disease,parkinsonian syndrome, L-DOPA induced dyskinesia, Tardive dyskinesia,dystonia, Huntington's disease, and Alzheimer's disease, which methodcomprises the step of administering to such a patient in need thereof atherapeutically effective amount of the phenoxy-ethyl-amine derivativeof claim 8, or a pharmaceutically acceptable salt thereof.
 12. Themethod of claim 11, wherein the disease or the disorder or the conditionis selected from the group consisting of schizophrenia, L-DOPA induceddyskinesia, and Huntington's disease.
 13. The method of claim 11,wherein the disease or the disorder or the condition is L-DOPA induceddyskinesia.
 14. A method of treatment of psychotic disorder of apatient, which method comprises the step of administering to such apatient in need thereof a therapeutically effective amount of thephenoxy-ethyl-amine derivative of claim 8, or a pharmaceuticallyacceptable salt thereof.
 15. A phenoxy-ethyl-amine derivative, whereinthe phenoxy-ethyl-amine derivative isN-ethyl-2-(3-fluoro-5-methylsulfonyl-phenoxy)ethanamine, or apharmaceutically acceptable salt thereof.
 16. The phenoxy-ethyl-aminederivative of claim 15, wherein the phenoxy-ethyl-amine derivative is ahydrochloric acid salt ofN-ethyl-2-(3-fluoro-5-methylsulfonyl-phenoxy)ethanamine.
 17. Apharmaceutical composition comprising a therapeutically effective amountof the phenoxy-ethyl-amine derivative of claim 15, or a pharmaceuticallyacceptable salt thereof, together with at least one pharmaceuticallyacceptable carrier, excipient, or diluent.
 18. A method of treatment ofa disease or a disorder or a condition of a patient, which disorder,disease or condition is selected from the group consisting of psychosis,schizophrenia, schizophreniform disorder, bipolar disorder, anxietydisorder, depression, obsessive-compulsive disease, dementia,age-related cognitive impairment, Autism spectrum disorders, ADHD,Gilles de la Tourette's syndrome, eating disorder, Parkinson's disease,parkinsonian syndrome, L-DOPA induced dyskinesia, Tardive dyskinesia,dystonia, Huntington's disease, and Alzheimer's disease, which methodcomprises the step of administering to such a patient in need thereof atherapeutically effective amount of the phenoxy-ethyl-amine derivativeof claim 15, or a pharmaceutically acceptable salt thereof.
 19. Themethod of claim 18, wherein the disease or the disorder or the conditionis selected from the group consisting of schizophrenia, L-DOPA induceddyskinesia, and Huntington's disease.
 20. The method of claim 18,wherein the disease or the disorder or the condition is L-DOPA induceddyskinesia.